Cannabinoids, which include the major psychoactive ingredient in marijuana, delta-9-tetrahydrocannabinol, have a long history of use for the treatment of pain. The mechanisms by which cannabinoids may reduce pain, however, remain largely unexplored. This proposal is focused on the mechanisms of cannabinoid inhibition of nociceptive signals relevant to head and face pain. The medullary dorsal horn receives nociceptive input from orofacial regions, and as the first site of neuronal integration represents a potentially critical target for the antinociceptive actions of cannabinoids. Behavioral experiments have demonstrated that intrathecal administration of a kappa opioid receptor antagonist blocks the antinociceptive effect of intrathecally administered cannabinoids, suggesting that inhibition of nociceptive signals produced by cannabinoid agonists require the release of an endogenous kappa opioid receptor agonist. The proposed experiments will compare the effect of cannabinoids on nociceptive neurons located in superficial versus deep laminae of the medullary dorsal horn. Furthermore, we will determine whether cannabinoids produce inhibition of medullary dorsal horn nociceptive neurons indirectly by stimulating the release of an endogenous kappa opioid receptor agonist. Using extracellular electrophysiological single unit recordings, we will compare the effect of cannabinoid receptor agonists applied directly to the medullary dorsal horn (bath application) on the activity of superficial and deep nociceptive neurons. Neuronal activity will be evoked by thermal stimulation of the receptive field. Stimulus response functions will be compared both prior to and following bath application of cannabinoid agonists. To determine whether cannabinoids indirectly modulate neuronal activity by inducing the release of an endogenous kappa opioid receptor agonist, cannabinoids will be tested in the presence of a kappa opioid receptor antagonist. Finally, the effect of a kappa opioid receptor agonist (bath application) on heat evoked activity of medullary dorsal horn neurons will be examined to allow for a direct comparison with kappa opioid receptor sensitive cannabinoid effects. The long-term objective of this research is to increase our understanding of the neuropharmacological mechanisms underlying cannabinoid-induced suppression of trigeminal pain and ultimately determine whether cannabinoids may be a useful class of medication for trigeminal pain patients as either a primary or adjuvant therapy.